Abuse potential reduction in abusable substance dosage form

ABSTRACT

The potential for substance abuse involving residual amounts of abusable substances remaining in used skin-worn patches is reduced by the provision of a system and method for combining the abusable substance with a separate anti-abuse substance agent as part of a removal or disposal procedure.

BACKGROUND OF THE INVENTION

I. Field of the Invention

The present invention relates generally to transdermal dosage forms foradministering substances of a class typically subject to abuse to thebody of a patient and, particularly, to reducing the potential for abuserelated to the use of such devices. More particularly, the inventioninvolves the use of binding agents to immobilize and prevent extractionof amounts of abusable substances remaining in transdermal patch devicesafter initial therapeutic transdermal administration to a patient. Othertechniques are also included.

II. Related Art

The temptation and potential for abuse by ingestion, injection, etc. ofnarcotics and other controlled substances is well known. This widespreadabuse issue is exemplified by the problems associated with fentanyl, thewidely used potent synthetic narcotic drug. Abuse of this drug hasbecome a significant issue among anesthesiologists and other hospitalworkers.

Of particular interest is the potential for abuse associated withtransdermal patch technology (passive or active) which is a preferredmethod of administration because it can eliminate the need for repeatedoral dosing. Unfortunately, with transdermal patches, significantamounts of drug compound remain in the patches after patients have wornthem for the prescribed period of time. The need for this excess amountof drug is well known, it is required to insure an adequate drivingforce in the transdermal application for the full wear time period. Forexample, in a published test of Duragesic (trademark of Johnson &Johnson) patches worn for the full 72-hour wear period, 28-84.4% of theoriginal loading of fentanyl still remained in the patches. The authorsof the study concluded that the residual dosage represented amountssufficient for abuse and misuse and was even potentially lethal.(Marquardt et al, Ann Pharmacother, 1995, 29:969-71). Using the 2002published consumption rate of fentanyl, an estimated 50 million or moreabusable, toxic dosages of fentanyl are released into the environmentannually.

Upon recognizing the need to deactivate residual fentanyl following thewearing of transdermal patches, researchers in a published studyrecommended that used patches be immersed in heated concentratedhydrochloric or sulfuric acid (Zambaux et. al. Ann Pharm Fr 2000, 58:176-179). This method was found to deactivate the residual. fentanyl bya hydrolysis chemical reaction. A significant disadvantage of thismethod is that it requires very hazardous materials and procedures.

Another approach to the reduction of abuse potential in transdermal drugadministration is found in U.S. Pat. No. 5,236,714. That documentdiscloses the combination of the drug with a co-formulated antagonistagent that is present in a form not releasable in the dosage form, butone which releases to prevent abuse of the composition by certain otherroutes of administration. Thus, the co-formulated antagonist does notpenetrate transdermally, but would be co-extracted during an attempt toextract the abusable material as by using solvents or by removing andingesting the combination. One disadvantage to this aproach resides inthe shelf-life complications associated with co-formulation of twoactive pharmaceutical ingredients in a transdermal patch. Anothersignificant limitation to this approach is that a used patch can stillbe abused with transdermal wear.

There still remains a need, then, for a safe and effective means ofpreventing abuse involving excess amounts of drugs, particularlyopioid-type drugs associated with transdermal administration of suchmaterials that protects against abuse by transdermal wear withoutrequiring hazardous materials.

SUMMARY OF THE INVENTION

By means of the present invention there is provided a system and methodfor reducing the potential for substance abuse in skin-worn transdermalpatch devices containing residual amounts of abusable substances afterremoval of the patch devices from a first user. The invention involvesthe use of a separate anti-abuse substance which may be a binding agentwhich immobilizes and deactivates the abusable substance on contactthereby reducing the potential for abuse. The anti-abuse substance mayalso contain an antagonist or irritant compound or, in certain cases,consist of an antagonist or irritant compound as will be describedbelow. The abuse prevention system of the present invention is generallyassociated with the removal and disposal of skin-worn patches and maytake any of several forms.

Preferred binding compositions include those binding agents which may beabsorbents for the abusable material. These agents immobilize theabusable substance and precludes future separation by normally availablemeans. Activated carbon has been found to be a material particularlysuitable for the adsorption of opioid compounds including syntheticopioids such as fentanyl. Thus, contacting these compounds with asuitable binding agent has been found to thereafter prevent extractionby normal solvents and other means readily available to prospectiveabusers.

One form of a system for reducing potential substance abuse in skin-worntransdermal patch devices containing residual amounts of abusablesubstances in accordance with the present invention includes adisposable container or pouch which has an opening configured to receivea skin-worn patch device after removal from a patient at the conclusionof the normal course of dosage administration. The container or pouch isprovided with an amount of an anti-abuse substance normally in the formof a binding agent selected for use with the particular abusablesubstance contained in the patch and is located in the container orpouch. When a skin-worn patch device is properly inserted into thecontainer or pouch, contact between the portion of the patch containingthe abusable substance and the binding agent will be made, therebyimmobilizing and deactivating the abusable substance. A closure devicefor closing the container or pouch is also provided so that thecontainer can also provide a closed system for disposing of the usedskin-worn patch. The closure system may include an adhesive seal or ziplock to seal the patch in the container.

In an alternative embodiment of the invention, a layer of absorbentmaterial such as activated carbon is provided in the patch itselfseparated from the layer containing the active ingredient by a lightlyadhering separation membrane. The separation membrane remains in placeduring the initial application and wearing of the patch but is providedwith an extension or connecting section which includes an amount ofadhesive near the end and which adhesively adheres to the skin of thepatient at the time the patch is applied. Removal of the patch leavesthe extension temporarily adhered to the skin and so causes theextension or connecting device to pull on and remove the separatormembrane from between the layer of anti-abuse substance or absorbentmaterial and the layer containing the active ingredient as the patch isremoved from the patient so that the two are brought into contact andthe remaining active ingredient is immobilized or absorbed by thebinding agent or absorbent, thereby rendering the remaining dosageharmless.

It should be recognized, then, that the primary objective of thisinvention lies in the prevention of drug-abusers from recovering drugsinto an abusable form, from a used transdermal patch. Accordingly, ithas been discovered that a binding agent, such as activated carbon, canprevent users from recovering drugs with use of commonly availablesolvents such as water, ethanol and mixtures thereof. However, someabusers may have access to less common solvents, some of which might beeffective in separation of the drug from the binding agent.

An option that can be selectively utilized in the present invention tofurther prevent abuse with the use of extraordinary solvents, is theincorporation of either antagonist or irritant compounds into a portionof the binding agent mix that will also be extracted. In this case, whenan abuser attempts to remove the drug from the binding agent, theantagonist and/or irritant is co-extracted along with the drug. As usedherein, an antagonist for an abusable substance is a compound orcomposition which acts upon or affects the user to essentially diminishor prevent the pharmacological effects of the abusable subject orgreatly delays such affects. As used herein, an irritant refers to anysubstance that causes inflammation following immediate, prolonged, orrepeated contact with skin or mucous membranes. Examples of suitableprotection agents include, without limitation, naloxone or naltrexone asantagonists and capsaicin or epicac as irritants.

In accordance with the invention, it is also possible to simply use aseparate antagonist and/or irritant layer in the place of a bindingagent. An advantage of this approach as compared to prior concepts suchas that of U.S. Pat. No. 5,236,714, cited above, is that the antagonistand/or irritant layer is designed to be kept separated from the drugduring storage and wear periods, thereby presenting an advantage from ashelf life stability perspective. However, the preferred deactivationmethod is one that additionally or principally incorporates a bindingmechanism.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings wherein like numerals depict like parts throughout thesame:

FIG. 1 is a simplified schematic view of one embodiment of the inventionshowing a patch and container system with parts omitted for clarity;

FIGS. 2 a and 2 b are simplified schematic drawings that depict analternate embodiment of the abuse potential reducing system of theinvention;

FIG. 3 is a plot showing a UV/VIS spectrophotometry scan of a 37.7 mg/lsolution of fentanyl citrate showing absorption from 200-240 nm;

FIG. 4 is a UV/VIS spectrophotometry scan plot of the solution of FIG.3, after 5 minutes of contact with activated carbon; and

FIG. 5 is a UV/VIS spectrophotometry scan plot of a 50% ethanol solutionutilized to attempt to extract adsorbed fentanyl citrate from theactivated carbon used to adsorb the fentanyl citrate in FIG. 4.

DETAILED DESCRIPTION

FIG. 1 depicts a skin-worn patch 10 of a class utilized with transdermaldelivery of an abusable substance such as an opioid. The patch isdepicted generally by 10 and includes a skin fasteningadhesive-containing layer 12 and an opioid-containing layer designed tocontact the skin at 14. A disposal container or pouch designed toaccompany the skin-worn patch 10 is shown generally by the referencecharacter 16 and includes a layer of absorbent material 18 attached toone side of the container 16 in the manner such that insertion of theused skin-worn patch 10 as is shown by the arrow 20 with the opioidlayer 14 facing the adsorptive material 18, ensures that contact willoccur between the layers 14 and 18, thereby adsorbing and deactivatingthe opioid from layer 14. The container 16 is also provided with a meansof sealing the patch 14 inside such as exemplified by adhesive strips 22on each side of the container. In this manner, the container 16containing the used patch 14 may then be thrown away with the knowledgethat the opioid material contained in the layer 14 of the skin-wornpatch 10 has been successfully deactivated by the adsorptive material inthe layer 18. In the case of opioids, this is preferably activatedcarbon.

The second embodiment is shown in FIGS. 2 a and 2 b. Those drawingsillustrate a simplified schematic representation of a skin-worn patch 30for the transdermal delivery of a therapeutic drug material such as anopioid contained in a layer 32. A layer containing an amount ofabsorbent material, such as activated carbon, is shown at 34. In FIG. 2a, the patch 30 is depicted as it would appear when applied to the skinof a patient and as it would appear during administration of theabusable substance to the patient. The patch is provided with a lightlyadhering or releasable separation membrane 36 which separates thesubstance to be administered in layer 32 from the absorbent material inlayer 34. The membrane 36 is attached to or is provided with anintegrally formed connector shown at 38 which contains an amount ofadhesive 40 which causes the connector 38 to adhere to the skin of apatient shown at 42. The normal patch adhesive overlayer which attachesthe patch to the skin is shown at 44.

FIG. 2 b depicts the patch 30 as it is being removed from the skin 42 ofa patient. Note that the removal of the adhesive layer 44 with the patchleaves the adhesive 40 with connector 38 still attached to the skin. Inthis manner, the connector 38 causes the separator membrane 36 to bepulled out from between the layers 32 and 34 thereby allowing theabsorbent material in layer 34 to contact the remaining amount of activeabusable substance in layer 32 deactivating the remaining amounts ofabusable substance in the patch.

FIG. 3 depicts a plot of a UV/VIS spectrophotometry scan of a 37.7 mg/lsolution of fentanyl citrate. The absorption from 200-240 nm is due tothe fentanyl citrate present in the solution, and the magnitude of theabsorbance is directly related to the dissolved concentration of thatcompound. It is readily seen that the concentration of the drug issignificant.

FIG. 4 represents a second UV/VIS spectrophotometry scan plot of thesolution of FIG. 3 after 5 minutes of contact with activated carbon.Note the dramatic reduction in the amount of absorption from 200-240 nm.The data shows that an estimated 97% of the fentanyl citrate had beenremoved from solution by 5 minutes of contact with activated carbon.Only 11 micrograms from the original content of 377 micrograms offentanyl citrate was remaining in solution.

The activated carbon utilized to adsorb the fentanyl citrate from thesolution of FIG. 3 was then taken and placed in a 50% ethanol/watersolution in an attempt to redissolve the adsorbed fentanyl citrate.

The plot of FIG. 5 represents another UV/VIS spectrophotometry scan ofthe 50% ethanol solution from which it appears that recovery of fentanylcitrate in the 50% ethanol solution was extremely low, i.e., less than5% of the drug was recovered. This indicates that the adsorption of thedrug onto the carbon was not only almost complete, but also verytenacious. Of the 366 micrograms of fentanyl citrate that was bound,only 13 micrograms was successfully separated in the attemptedextraction process.

It should further be noted that the layer of absorbent material 18 inFIG. 1 and the layer 34 of absorbent material in FIGS. 2 a and 2 b canbe selectively provided with an antagonist and/or an irritant materialthat goes into solution with the opioid or other abusable drug ofinterest in order to provide further means of abuse protection. In thosecases where abusers have access to less commonly available solvents,which could possibly be used to separate the drug of interest from thebinding agent, the antagonist and/or irritant compounds serve as addedabuse resistance protection. It is also contemplated that under somecircumstances antagonist and/or irritant compounds might replace thebinding agent entirely as the active anti-abuse substance or ingredientof the layers 18 and 34.

This invention has been described herein in considerable detail in orderto comply with the patent statutes and to provide those skilled in theart with the information needed to apply the novel principles and toconstruct and use such specialized components as are required. However,it is to be understood that the invention can be carried out byspecifically different equipment and devices, and that variousmodifications, both as to the equipment and operating procedures, can beaccomplished without departing from the scope of the invention itself.

1. A disposal system for a skin-worn transdermal patch device containingresidual amount of an abusable opioid substance after use thereof on apatient, said system comprising: (a) a disposal container separate fromand independent of said skin-worn patch device and having an openingtherein for receiving said skin-worn patch device; (b) a deactivationsystem in said container comprising material that deactivates andrenders unusable said abusable opioid substance on contact, comprising:(1) a first amount of carbon in an activated state in a quantitysufficient to bind said abusable opioid substance in said patch; (2) asecond amount of carbon that has been pre-incorporated with a speciesthat is releasable from said second amount of carbon upon solventextraction and wherein said species is selected from the groupconsisting of capsaicin, ipecac, naloxone and naltrexone andcombinations thereof such that said species remains with said abusableopioid substance upon extraction thereby rendering said abusable opioidsubstance unusable; and (c) closure device for closing said disposalcontainer thereby capturing said skin-worn patch device.
 2. A system asin claim 1 wherein said container is in the form of a flexible pouch. 3.A system as in claim 1 wherein said closure device includes an adhesiveseal.
 4. A system as in claim 2 wherein said closure device includes anadhesive seal.
 5. A system as in claim 1 wherein said opioid abusablesubstance comprises fentanyl.
 6. A disposal system as in claim 1 whereinextraction solvents are water, ethanol and combinations thereof.
 7. Adisposal system as in claim 1 wherein said species includes capsaicin.8. A disposal pouch for the deactivation of a used opioid transdermalpatch comprising a deactivation system in said container comprisingmaterial that deactivates and renders unusable said abusable opioidsubstance on contact, comprising: (a) a first amount of carbon in anactivated state in a quantity sufficient to bind said abusable opioidsubstance in said patch; (b) a second amount of carbon that has beenpre-incorporated with a species that is releasable from said secondamount of carbon upon solvent extraction and wherein said species isselected from the group consisting of capsaicin, ipecac, naloxone andnaltrexone and combinations thereof such that said species remains withsaid abusable opioid substance upon extraction thereby rendering saidabusable opioid substance unusable; and (c) a container in the form of apouch.